Excitatory neurotransmission in the mammalian central nervous system (CNS) is primarily mediated by the amino acid, L-glutamate, acting on ionotropic and metabotropic receptors. The ionotropic receptors, which respond to this amino acid, have been divided into the N-methyl-D-aspartate (NMDA) receptors, the alfa-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, and the kainic acid (KA) receptors. Moreover molecular biological studies have established that these receptors are composed of subunits that can assemble to form functional channels, and a number of such subunits have been identified.
This way it has been established that the AMPA receptors are assembled from four protein subunits known as GluR1 to GluR4, while the KA receptors are assembled from subunits known as GluR5 to GluR7, KA-1 and KA-2.
Due to their distribution in different mammalian tissues, the GluR5 receptors and the substances acting thereon have drawn particular attention.
WO 94/22807 describes urea and amide derivatives useful as potassium channel openers.
WO 97/45400, WO 97/45111, WO 98/47879 and WO 00/24707 describe diphenyl urea derivatives containing an acidic group and their use as chloride channel blockers.
WO 02/039987 describes the use of diphenyl urea derivatives as malaria anion channel blockers for treating malaria.
WO 02/064128 describes the use of diphenyl urea derivatives for modulation of the association of caspase-9 to Apaf-1 for the treatment of diseases characterised by excessive or insufficient cell death.
WO 02/070467 describes diphenyl urea derivatives useful as inhibitors of intracellular protein-degradation pathways.
However, use of diphenyl urea derivatives as ionotropic GluR5 receptor modulators have never been described.